Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injury‐dependent and reactivated developmental processes

Abstract

One of the most striking features of the injured mature peripheral nervous system is the ability to regenerate. The lesioned peripheral nervous system displays stereotypic histopathological reactions indicating the activation of a co-ordinated lesion-induced gene expression programme. Previous research has already identified molecular components of this axonal switch from a mature transmitting to a regenerative growth mode. The observed alterations in gene expression within the lesioned distal nerve stump were largely attributed to recapitulated developmental processes. However, to our knowledge, this hypothesis has not been proven systematically. Most of the stereotypic molecular and cellular reactions during nerve development and repair can be assigned to specific time windows. Consequently, we have compared gene expression profiles of both paradigms at six different time-points each by means of cDNA array hybridization. Our data identified injury-specific molecular reactions and revealed to what extent developmental mechanisms are reactivated in response to nerve lesion. Ninety-one genes (47% of the regeneration-associated genes) were found to be significantly regulated in both paradigms, suggesting that regeneration only partially recapitulates development and that approximately half of the regulated genes are part of a regenerationdependent programme. Interestingly, mainly genes encoding signal transducers or factors involved in processes such as cell death, immune response, transport and transcriptional regulation showed injury-specific gene expression. Keywords: cDNA array analysis, development, gene expression profiling, nerve injury, sciatic nerve regeneration. Adult peripheral nerves in mammals have an intrinsic capacity to regenerate after axotomy. This spontaneous regeneration potential distinguishes the peripheral nervous system from the CNS. Recent advances in the study of peripheral nerve regeneration have revealed that successful neuronal survival and target reinnervation depend on both the intrinsic regenerative capacity of peripheral axons and the presence of a growth-permissive environment.DNA array-based expression profiling allows identification of the spectrum of genes expressed during peripheral nerve regeneration. Recently, several studies were published describing axotomy-induced changes in peripheral nerve gene expression. However, these studies mainly focused on those transcriptional changes that were induced in the cell bodies of the axotomized sensory or spinal motor neurones (Fan et al. 2001;Kim et al. 2001;Bonilla et al. 2002;Costigan et al. 2002;Nagarajan et al. 2002;Xiao et al. 2002;Cameron et al. 2003). Besides a previous study published by our laboratory (Bosse et al. Abbreviations used: ApoD, apolipoprotein D; AP-1, adaptor protein complex AP-1; ATF, activating transcription factor; bcl2, apoptosis regulator protein Bcl-2 like protein 1; BMP-2, bone morphogenic protein; bZIP, basic leucine zipper transcription factor; C/EBPd, CCAAT/ enhancer binding protein delta; CREB...

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

“…Axons begin to grow into the distal endoneurial tubes 1 week after nerve injury [6,39,45] ; Schwann cell/axon contacts are re-established and remyelination occurs at about 2 weeks; and the proper target tissues are reinnervated at about 4 weeks after sciatic nerve injury. In this process, a large number of genes with marked up-or down-regulation were differentially expressed, indicating sustained regulation at consecutive time points, meaning regeneration/repair by means of a continuously progressive program [4,10,35] .…”

“…In this process, a large number of genes with marked up-or down-regulation were differentially expressed, indicating sustained regulation at consecutive time points, meaning regeneration/repair by means of a continuously progressive program [4,10,35] . Nerve regeneration mainly consists of nerve repair and tissue re-innervation after injury [45,46] . The activated injury-dependent process is regulated initially following the genetic response featuring degeneration and regeneration.…”

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…However, what is critical for the biology of regeneration and for a possible regeneration therapeutic agent is whether the underlying molecular profile of CNS regeneration recapitulates the molecular profile of neurodevelopment. Initial transcriptional profiling of neurons that form new connections after stroke, retinal ganglion cells that regenerate an injured axon in the optic nerve, or dorsal root ganglion cells that regrow a connection after peripheral nerve injury suggest some overlap with genes that are active in the developing nervous system, but overall a distinct set of genes that is regulated in these injury responses 11, 122. However, direct comparison of the transcriptome of neurons exposed to a regenerating stimulus after stroke and the transcriptomes of neurons at several stages of neuronal development from many different laboratories clearly indicates that the molecular expression profile of regeneration is statistically and fairly dramatically distinct from the developmental transcriptome 13.…”

Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration

“…Lesioning the peripheral axonal branches of DRG neurons causes expression of a distinct set of genes, termed regeneration-associated genes, which are not upregulated after central lesioning (Ylera and Bradke, 2006). Interestingly, those sets of genes contain direct and indirect regulators of microtubule polymerization and stabilization, including tubulin isoforms, MAPs (microtubule- associated proteins), and arginase I (Miller et al, 1989;Moskowitz and Oblinger, 1995;Cai et al, 2002;Bosse et al, 2006), which may enhance the rapid regrowth of lesioned PNS axons. Notably, it has been demonstrated that interfering with the expression of microtubule binding proteins inhibits neurite outgrowth (Caceres et al, 1992).…”